IGF-I Receptor Mutations and Intrauterine and Postnatal Growth Retardation
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《新英格兰医药杂志》
To the Editor: Abuzzahab et al. (Dec. 4 issue)1 describe two children with sequence changes in the gene encoding the insulin-like growth factor I (IGF-I) receptor and conclude that these mutations caused their growth retardation. One child had two missense mutations, and only 43 controls were evaluated (half the number generally accepted). The second child had a single nonsense mutation, and no data from controls are reported. Apparently, the assumption is that a nonsense mutation must be pathogenic. Although data from mice are not necessarily equivalent to data from humans, heterozygous IGF-I receptor knockout mice do not exhibit growth retardation.2 In addition, Patient 2 in the report by Abuzzahab et al. had developmental delay, dysmorphic features, and quite possibly a syndromic diagnosis that accounts for all his features. I suggest that caution is needed in the interpretation of the reported sequence changes.
Sheila Unger, M.D.
Hospital for Sick Children
Toronto, ON M5G 1X8, Canada
sheila.unger@sickkids.ca
References
Abuzzahab MJ, Schneider A, Goddard A, et al. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med 2003;349:2211-2222.
Holzenberger M, Dupont J, Ducos B, et al. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 2003;421:182-187.
The authors reply: In our description of a new syndrome caused by mutations in the gene encoding the IGF-I receptor, we found unmistakable IGF-I resistance, manifested as elevated circulating concentrations of IGF-I. In the patient who had altered amino acids within the IGF-I binding domain, defects in binding and reduced sensitivity to IGF-I–stimulated receptor phosphorylation in fibroblasts confirmed the receptor dysfunction. It is extremely unlikely that a patient with those defects would have growth failure from an unrelated, unapparent cause. Her mutations were not found in the 84 other subjects (43 controls and 41 children with intrauterine growth retardation).
In the patient who had a monoallelic nonsense mutation, the genetic defect associated with subnormal stature in other family members and with reduced abundance of cell-surface IGF-I receptor was identified. Though haploinsufficient mice often grow normally, mice in which the abundance of IGF-I receptors is genetically reduced to less than 50 percent of normal are small,1 suggesting that mice are simply less sensitive than humans to reductions in IGF-I signaling. Though we do not necessarily attribute every clinical feature to the mutations, a picture emerges in which gradations of IGF-I–receptor hypofunction attenuate human growth.
Steven D. Chernausek, M.D.
Cincinnati Children's Hospital Medical Center
Cincinnati, OH 45229
steven.chernausek@cchmc.org
Wieland Kiess, M.D.
Hospital for Children and Adolescents
D-04317 Leipzig, Germany
Robert J. Smith, M.D.
Hallet Center for Diabetes and Endocrinology
Providence, RI 02903
References
Holzenberger M, Hamard G, Zaoui R, et al. Experimental IGF-I receptor deficiency generates a sexually dimorphic pattern of organ-specific growth deficits in mice, affecting fat tissue in particular. Endocrinology 2001;142:4469-4478.
Sheila Unger, M.D.
Hospital for Sick Children
Toronto, ON M5G 1X8, Canada
sheila.unger@sickkids.ca
References
Abuzzahab MJ, Schneider A, Goddard A, et al. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med 2003;349:2211-2222.
Holzenberger M, Dupont J, Ducos B, et al. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 2003;421:182-187.
The authors reply: In our description of a new syndrome caused by mutations in the gene encoding the IGF-I receptor, we found unmistakable IGF-I resistance, manifested as elevated circulating concentrations of IGF-I. In the patient who had altered amino acids within the IGF-I binding domain, defects in binding and reduced sensitivity to IGF-I–stimulated receptor phosphorylation in fibroblasts confirmed the receptor dysfunction. It is extremely unlikely that a patient with those defects would have growth failure from an unrelated, unapparent cause. Her mutations were not found in the 84 other subjects (43 controls and 41 children with intrauterine growth retardation).
In the patient who had a monoallelic nonsense mutation, the genetic defect associated with subnormal stature in other family members and with reduced abundance of cell-surface IGF-I receptor was identified. Though haploinsufficient mice often grow normally, mice in which the abundance of IGF-I receptors is genetically reduced to less than 50 percent of normal are small,1 suggesting that mice are simply less sensitive than humans to reductions in IGF-I signaling. Though we do not necessarily attribute every clinical feature to the mutations, a picture emerges in which gradations of IGF-I–receptor hypofunction attenuate human growth.
Steven D. Chernausek, M.D.
Cincinnati Children's Hospital Medical Center
Cincinnati, OH 45229
steven.chernausek@cchmc.org
Wieland Kiess, M.D.
Hospital for Children and Adolescents
D-04317 Leipzig, Germany
Robert J. Smith, M.D.
Hallet Center for Diabetes and Endocrinology
Providence, RI 02903
References
Holzenberger M, Hamard G, Zaoui R, et al. Experimental IGF-I receptor deficiency generates a sexually dimorphic pattern of organ-specific growth deficits in mice, affecting fat tissue in particular. Endocrinology 2001;142:4469-4478.